Passiflora Incarnata L.: Ethnopharmacology, Clinical Application, Safety and Evaluation of Clinical Trials

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Passiflora incarnata L.: Ethnopharmacology, clinical application, safety and evaluation of clinical trials

Article in Journal of ethnopharmacology · October 2013 DOI: 10.1016/j.jep.2013.09.047 · Source: PubMed

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Review Passiﬂora incarnata L.: Ethnopharmacology, clinical application, safety and evaluation of clinical trials$

M. Miroddi a, G. Calapai a,b,n, M. Navarra c, P.L. Minciullo a,d, S. Gangemi a,d,e a Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy b Operative Unit of Clinical Pharmacology, Azienda Ospedaliera Universitaria Policlinico “G. Martino”, Messina, Italy c Department of Drug Sciences and Health Products, University of Messina, Messina, Italy d Operative Unit of Allergy and Clinical Immunology, Azienda Ospedaliera Universitaria Policlinico “G. Martino”, Messina, Italy e Institute of Biomedicine and Molecular Immunology “A. Monroy” (IBIM), Consiglio Nazionale Delle Ricerche (CNR), Palermo, Italy article info abstract

Article history: Ethnopharmacological relevance: The genus Passiflora incarnata Linnaeus comprises approximately Received 5 July 2013 520 species belonging to the Passifloraceae family. The majority of these species are vines found in Received in revised form Central or South America, with rare occurrence in North America, Southeast Asia and Australia. The 23 September 2013 genus Passiflora incarnata has long been used in traditional herbal medicine for the treatment of Accepted 24 September 2013 insomnia and anxiety in Europe, and it has been used as a sedative tea in North America. Furthermore, Available online 17 October 2013 this plant has been used for analgesic, anti-spasmodic, anti-asthmatic, wormicidal and sedative purposes Keywords: in Brazil; as a sedative and narcotic in Iraq; and for the treatment of disorders such as dysmenorrhoea, fl Passi ora incarnata epilepsy, insomnia, neurosis and neuralgia in Turkey. In Poland, this plant has been used to treat hysteria Insomnia and neurasthenia; in America, it has been used to treat diarrhoea, dysmenorrhoea, neuralgia, burns, Sleep disorders haemorrhoids and insomnia. Passiflora incarnata L. has also been used to cure subjects affected by opiate Anxiety dependence in India. This review aims to provide up-to-date information about the pharmacology, clinical efficacy and clinical safety of Passiflora incarnata L. based on the scientific literature. In particular, the methodological accuracy of clinical trials is analysed in accordance with current consolidated guidelines on reporting the clinical efficacy of herbal medicine, offering new insight into opportunities for future research and development. Methods: A bibliographic investigation was performed by examining the available data on Passiflora incarnata L. from globally accepted scientific databases and search engines (Pubmed, Scopus and Web of Science, SciFinder and Google Scholar). We selected studies, case reports, and reviews addressing the pharmacology and safety of Passiflora incarnata. Results: Although numerous Passiflora incarnata L. derivative products have been commercialised as alternative anxiolytic and sedative remedies based on their long tradition of use, their supposed efficacy does not appear to be adequately corroborated by the literature, with clinical studies often featuring inadequate methodologies and descriptions of the products under investigation. This medicinal plant has shown a wide spectrum of pharmacological activities in preclinical experiments, including anxiolytic, sedative, antitussive, antiasthmatic, and antidiabetic activities. The plant has a good safety profile. The clinical trials that we included in this review were designed to evaluate and in some cases confirm promising observations of preclinical pharmacological activity, and the methodological limits of these studies are characterised here. Conclusion: In conclusion, clinical studies on the effects of products containing herbal preparations based on Passiflora incarnata reveal crucial weaknesses such as poor details regarding the drug extract ratio, limited patient samples, no description of blinding and randomisation procedures, incorrect definition of placebo, and lack of intention to treat analysis. In conclusion, the results of this review suggest that new clinical trials should be conducted using a more rigorous methodology to assess the traditional putative efficacy of Passiflora incarnata L. & 2013 Elsevier Ireland Ltd. All rights reserved.

☆Chemical compounds studied in this article Chrysin (PubChem CID: 5281607); Vitexin (PubChem CID: 5280441); Isovitexin (PubChem CID: 25202038); Kaempferol (PubChem CID: 5280863); Harman (PubChem CID: 5281404); Harmine (PubChem CID: 5280953); Harmaline (PubChem CID: 5280951); Palmitic Acid (PubChem CID: 985); Apigenin (PubChem CID: 5280443); Myristic Acid (PubChem CID: 11005). n Corresponding author at: Department of Clinical and Experimental Medicine, Via Consolare Valeria, 5 Torre Biologica 51 piano, Policlinico “G. martino”, 98125 Messina, Italy. Tel.: þ39 0902213646; fax: þ39 0902213000. E-mail address: [email protected] (G. Calapai).

Contents

1. Introduction ...... 792 2. Research method and inclusion criteria ...... 792 3. Botanical description ...... 792 4. Traditional use/ethnomedicinal uses ...... 793 5. Phytochemistry ...... 793 6. Preclinical data supporting pharmacological effects ...... 795 7. Overview of clinical studies ...... 795 8. Anxiety (general anxiety disorder and pre-operative anxiety) ...... 799 9. Treatment of opiate withdrawal ...... 800 10. Treatment of menopausal symptoms ...... 801 11. Treatment of insomnia/sleep disorders ...... 801 12. Treatment of ADHD ...... 802 13. Safety proﬁle and pharmacovigilance data...... 802 14. Conclusion...... 802 References...... 803

1. Introduction 2008). This review also highlights the scientificbasisforfuture research on Passiflora incarnata, and its real potential for the This article summarises and critically analyses the scientific development of the market for herbal medicinal products. literature on Passiflora incarnata L. (English common name: passionflower), an herbal medicine with a long tradition of medicinal use worldwide. The genus Passiflora incarnata L. com- 2. Research method and inclusion criteria prises approximately 520 species of dicotyledonous plants belonging to the family Passifloraceae (Wohlmuth et al., 2010). Two investigators independently conducted a systematic search of The word Passiflora comes from the Latin word “Passio” the scientific literature published prior to December 2012 regarding because in 1529, Spanish “conquistadores” described its flowers Passiflora incarnata L. using MEDLINE, the Cochrane library, EMBASE as symbols of the “passion of Christ” (Kinghorn, 2001; Dhawan and Google Scholar. The investigators used the following keywords or et al., 2004). The majority of these species are vines, with most combinations of them: found in Central or South America and some species occurring in North America, Southeast Asia and Australia (Ulmer et al., 2004). A Passiflora number of species, including Passiflora edulis Sims and Passiflora Passiflora incarnata laurifolia L., are widely cultivated for their edible fruits, while Passionflower many others are grown as ornamentals for their particular and Maypop spectacular flowers (Wohlmuth et al., 2010). Several species have a long history of use as traditional herbal medicines. Passiflora The articles included in the analysis were reviews, meta-analyses, incarnata L., which originated in North America, is the most clinical trials, and case reports. The selected articles report tradi- common variety used in contemporary Western phytotherapy. tional uses of Passiflora incarnata, assess its phytochemistry, present This species, commonly known by the English name maypop, is both in vitro and in vivo preclinical experimental evidence, and native to the south-eastern United States, but is also cultivated in present clinical evidence regarding its efficacy and safety profile. Europe, Asia, Africa and Australia, both as an ornamental and as a We excluded clinical trials of treatments with herbal medicine medicinal plant (Dhawan et al., 2004). combinations containing Passiflora incarnata extracts, or based on This plant exhibits various pharmacological properties and only one active compound from the phytocomplex of the plant. possesses a complex phytochemistry. The present review aims to Scientific literature in English, German, French, Spanish and other evaluate and comment on the scientific evidence regarding the languages has been considered, although in the case of one article therapeutic use of Passiflora incarnata, to summaries the chemical in Chinese (Zhou et al., 2008), we could only evaluated the abstract constituents of therapeutic preparations, to analyse the pharma- written in English. We included recently published studies. cological aspects of the plant by examining both preclinical and clinical research, and to assess the toxicity and safety profile. The putative clinical efficacy of Passiflora incarnata has been 3. Botanical description evaluated for the treatment of a variety of diseases, but the current most common use in clinical practice is in the treatment of anxiety Passiflora edulis Sims has often been taken to be synonymous with and sleep disorders. Passiflora incarnata L. (www.plantlist.org, last accessed December In several preclinical experiments, Passiflora extracts have exhib- 2012) because the plants possess identical morphological and ited potential effects for the treatment of anxiety and insomnia as microscopic characteristics. Passiflora edulis, as the name of the well as for attention-deficit hyperactivity disorder, hypertension and species reflects, is mainly cultivated for edible purposes and does cancer. Recent studies also showed that preparations obtained from not exert pharmacological effects on the central nervous system. leaves exert anticonvulsant effects (Dhawan, et al. 2003a; Nassiri-Asl Although one article attempted to eliminate potential confusion et al., 2007). Although a variety of other preparations are available, between these two similar plants (Dhawan et al., 2001b), this dried extracts are the most important product derived from passion- confusion remains, potentially leading to the selection of the wrong flower. Many practitioners actually use passionflower extracts alone plant, thus accounting for the inconclusive and contradictory phar- or in combination with other herbal medicines to treat anxiety and macological reports on these two plants. Dhawan et al. established sleep disorders in a wide range of patients (Newall, 1996; Zhou et al., key identification parameters to differentiate between the two M. Miroddi et al. / Journal of Ethnopharmacology 150 (2013) 791–804 793 plants: various leaf constants, the vein-islet number, the vein- (Flos passionis) acquired its name from the descriptions of the termination number, the stomatal number, and the stomatal index; parts of its flower by Spanish missionaries in South America. It was as well as physicochemical parameters such as ash values, extractive known by the Spanish as ‘La Flor de las Cinco Llagas’ or the ‘The values, and the thin layer chromatography profile of the petroleum Flower With The Five Wounds.’‘Passionis’ refers to Christ's ether extracts of Passiflora incarnata and Passiflora edulis (Dhawan passion, representing various elements of the Crucifixion (Ratsch, et al., 2001b). 1998). Early European travellers in North America noted that the Passiflora incarnata is an evergreen climber, rapidly growing up Algonquin Indians in Virginia and the Creek people in Florida ate to 6 m (19 ft 8 in). This plant is in leaf from December to January, the fruits of Passiflora incarnata from cultivated as well as wild in flower from June to July, and its seeds ripen from September to sources. They wrote in a report: “they plant also the field apple, the November. This plant possesses hermaphrodite flowers (posses- maracock, a wyld fruict like a kind of pomegranett, which increaseth sing both male and female organs) which are pollinated by insects infinitlye, and ripens in August” (Major 1849:72). Passionflower was such as bees. Passiflora incarnata can grow in light (sandy), brought to Europe, where it became widely cultivated and was medium (loamy) or heavy (clay) soils, with a preference for introduced to European folk medicine, becoming a popular tradi- well-drained soil, and it cannot grow in the shade due to the soil tional phyotherapeutic remedy as well as a homoeopathic remedy moisture in shady areas. for the relief of mild symptoms of mental stress, anxiety and mild Description of the different parts of the plant sleep disorder (Beverley, 1947; Bradley, 1992; EMA AR 2008; European Pharmacopeia 7th Edition). Traditional medicinal use in Europe has – Stems – Vining, glabrous to minutely pubescent, herbaceous. been documented continuously in several books published in 1938, Tendrils present. 1958, 1977 and 2003 (Madaus, 1938; Hoppe, 1958; List and – Leaves – Alternate, 3-lobed, serrulate, petiolate, up to þ15 cm Hörhammer, 1977; ESCOP, 2007). Today, passionflower is officially long, þ13 cm wide, glabrous. Petioles with two glands near the included in the national pharmacopeias of France, Germany, and base of the leaf blade. Switzerland and is also monographed in the British Herbal Pharma- – Inflorescence – Single pedicillate flowers from leaf axils. copoeia and the British Herbal Compendium, the ESCOP monographs, – Flowers – A corona consisting of a structure of appendages the Community Herbal Monographs of the EMA, the German Standard situated between the corolla and the stamens. As shown in the Licences, the German Homoeopathic Pharmacopoeia, the Homoeo- graphical abstract, the corona is the ring-like structure of pathic Pharmacopoeia of the United States, and the Pharmacopeia of purple and white appendages above the petals and sepals. Egypt (VA, 1978, 1987, 1992, 1996, 1997; Dhawan et al., 2004). In The flower is typically 6–7 cm in diameter. The flower has European traditional medicine, passionflower has long been pre- 5 petals and 5 sepals, which are purplish to whitish, similar, scribed for various indications such as anxiety, nervousness, constipa- and alternating. The flower has 3 styles, typically 3 stamens, tion, dispepsia, mild infections and insomnia. In Poland, it has been 5 greenish-white sepals with terminal appendages. prescribed to cure disorders such as hysteria and neurasthenia. – Fruit – Fleshy, ovoid to globose, initially green, yellowish-red at Presently, Passiflora incarnata is commonly used in phytotherapy as a maturity. mild sedative and anxiolytic. The botanical drugs included in the – Flowering – June – September. current European and British Pharmacopoeias are the dried aerial – Habitat – Thickets, waste ground, disturbed sites, roadsides, parts of the plant (Taylor, 1996; Wohlmuth et al., 2010). In Turkey, railroads. The plant is also cultivated (ESCOP, 1997). passionflower is used for the following conditions: dysmenorrhoea, epilepsy, insomnia, neurosis and neuralgia (Taylor, 1996). In South America, it is still commonly used in folk medicine. In Argentina and Mexico, it is currently consumed for its sedative effects (Rodriguez- 4. Traditional use/ethnomedicinal uses Fragoso, et al., 2008); in Brazil it is used as an analgesic, anti- spasmodic, anti-asthmatic, wormicidal and sedative (Taylor, 1996). In The prehistoric use of Passiflora incarnata can be dated back to North America, it is used for the treatment of diarrhoea, premenstrual the Late Archaic period in North America, which ranges between syndrome, dysmenorrhoea, neuralgia, burns, haemorrhoids, insomnia, 8000 and 2000 B.C. Archaeological evidence indicates that native muscle cramps, hysteria, neuralgia, and as a pain reliever for various Americans developed human-plant mutualism during the pre- conditions. Native Americans still continue to use this plant in folk Colombian period, and Passiflora incarnata was a common weed medicine, with Cherokees consuming the root tea as a tonic for the crop that often occurred in anthropogenic habitats. Ethnobotanists liver and for skin boils. The roots are pounded for topical anti- hypothesised that passionflower represented a minor food plant inflammatory use. It is also used for nervousness, abdominal cramps for native Americans rather than a staple, and for this reason the and anxiety (Dhawan et al., 2004). Passiflora incarnata is also used as mutualism occurred without any intentional behaviour such as an herbal medicine in Asia; it has been used to treat morphine planting, seed storage, or cultivation. The two important aspects of dependence in traditional medicine in India (Ingale and Hivrale, 2010). seed dispersal and environmental modification can explain the In Vietnam, it has been used for sleeplessness, anxiety and high blood geographic diffusion of Passiflora incarnata in various areas in North pressure (Van Dan and Chuong, 1990). In the African countries of America, despite the demographic decline of the aboriginal popula- Rwanda, Kenya and Congo it is employed as a folk remedy by tion and the subsequent replacement by European–American herbalists and natural health practitioners for its sedative, nervine, populations characterised by different dietary and agricultural anti-spasmodic and analgesic effects (Neuwinger, 2000). It has been traditions. In addition, the horticultural practice of raising this plant used as a sedative and narcotic in Iraq, and it is cultivated and as ornamental because of its spectacular flowers contributed to commonly prescribed in Australia as a sedative and anxiolytic extending its presence in North America (Gremillion, 1989; Iwu, (Wohlmuth et al., 2010). 2002). In American aboriginal medicine, the passionflower has been used in particular by the Cherokees of the southern Allegheny mountains, the Houmas of Louisiana and the Aztecs of Mexico 5. Phytochemistry (Vogel, 1977; Taylor, 1996). Spanish conquerors first learned of passionflower from pre- A considerable body of literature has explored the chemical Colombian people who traditionally used it as a sedative to treat composition of the raw material and of various products derived insomnia and nervousness. Passiflora incarnata or ‘Passionflower’ from passionflower. 794 M. Miroddi et al. / Journal of Ethnopharmacology 150 (2013) 791–804

The results of this literature clearly show that various bioactive Table 1 constituents can contribute to the reported clinical effects, prob- Main flavonoids as secondary compounds of Passiflora incarnata L. phytocomplex. ably in a synergistic manner. Currently, researchers believe that Flavonoid Molecular formula Skeletal formula only a portion of the pharmacologically active compounds have fi been precisely identi ed (Abourashed et al., 2002; Grundmann Chrysin C15H10O4 et al., 2008; Zucolotto et al., 2012). The aerial parts of Passiflora incarnata. are phytochemically characterised by the presence of a pattern of several primary constituents consisting of flavonoids, maltol, cyanogenic glycosides and indole alkaloids (Poethke et al.,

1970; Spencer and Seigler, 1985, Qimin et al., 1991; Krenn, 2001; Vitexin C21H20O10 Marchart et al., 2003). The indole alkaloids are represented by harman, harmin, harmalin, harmol and harmalol, which can act as monoamino-oxidase inhibitors, but they are present in small amounts (Poethke et al., 1970; Spencer and Seigler, 1985; Rehwald et al., 1995; Sampath et al., 2011). Flavonoids represent 2.5% of the compounds in this plant (Table 1), with vitexin, isovitexin, orientin, isoorientin, apigenin, kaempferol, Isovitexin C21H20O10 vicenin, lucenin and saponarin identified (Lutomski et al., 1981; Krenn, 2001; Marchart et al., 2003). Furthermore, phenolic, fatty, linoleic, linolenic, palmitic, oleic and myristic acids are present, as well as formic and butyric acids, coumarins, phytosterols and essential oils (Sampath et al. 2011; Bruneton, 1995; di Wohlmuth 2010). Orientin C21H20O11 Different groups of researchers from Australia, Austria, Germany, Italy, and other countries have carried out analytical studies on different Passiflora incarnata samples with the goal of verifying and assessing the putative variability in C-glycosyl flavone content. This issue is important because some of the C- glycosyl flavones are considered to be marker compounds useful to Isoorientin C21H20O11 distinguish between different passionflower extracts. Samples analysed in these experiments had different origins and different destination markets (e.g., Germany, Austria, USA, etc.) the results showed considerable qualitative and quantitative variability with fl respect to C-glycosyl avone content (Raffaelli et al.,1997; Apigenin C15H10O5 Yockteng et al., 2011). In 2004, Pereira et al. developed a high-performance thin layer chromatographic (HP-TLC) method to quantitatively determine the flavonoid contents in leaves of Passiflora alata, Passiflora edulis, Passiflora caerulea and Passiflora incarnata. The orientin and Kaempferol C15H10O6 isoorientin contents were determined, and the results were compared with those obtained using a quantitative HPLC-UV method. The authors reported qualitative and quantitative differences in flavonoid content among different Passiflora incarnata and other Passiflora species (Pereira et al., 2004). Wohlmuth et al. performed analytical tests using thin layer chromatography (TLC), high performance liquid chromatography (HPLC) with photodiode array detection and liquid chromatography–mass spectrometry active substances. Flavonoids present in Passiflora incarnata seem LC/MS on 11 samples of Passiflora incarnata pharmaceutical raw to have a pharmacological profile similar to that of prodrugs, material obtained from different Australian cultivations. These which require metabolic activation (Vissiennon et al., 2012). data indicated little variability, in contrast with previous results Various experiments assessed the pharmacological activities of published by other authors. According to their analytical assess- a tri-substituted benzoflavone compound, termed BZF. The results ment, the isovitexin chemotype is the most common in commer- regarding the potential beneficial effects of BZF against anxiety cialised plants (Wohlmuth, 2010). were not conclusive, even though BZF-like compounds are only Seminal studies attributed an anti-anxiety action to Passiflora present in trace amounts in some passionflower extracts (Dhawan incarnata flavonoids, but recently published data revised this role, et al., 2001a; Holbik et al., 2010; Sampath et al., 2011). Addition- suggesting that these compounds do not contribute exclusively to ally, Elsas et al. (2010) repeated TLC and LC analytical examination the anxiolytic activity and that other substances are likely respon- according to the methodology described in other studies (Dhawan sible for this effect as well. Recently, in vivo and in vitro studies et al., 2003a; Dhawan et al., 2004). These authors did not detect demonstrated that flavonoids can be metabolised by the intestinal any substances matching BZF compounds in the analysed extracts, microflora to their corresponding hydroxyphenylacetic acids; the and revealed little variation in the relative abundance of specific route of administration has been demonstrated to determine the flavonoids (Elsas et al., 2010). The Passiflora incarnata extracts biological activity of flavonoids. For example, when kaempferol were found to contain a certain amount of gamma-aminobutyric and quercetin are administered intraperitoneally in mice, they do acid (GABA) (Carratù et al. 2008), suggesting that the bioactivity of not exert anxiolytic effects. Vissiennon et al. hypothesised that this plant could result from the synergistic action of GABA with anxiolytically active flavonoids like kaempferol have to be meta- additional phytochemicals that may facilitate membrane permea- bolised by bacteria in the gut and that the resulting phenylacetic tion, leading to the positive modulation of GABAA receptors by acid derivative metabolites could be the main pharmacologically flavonoids (Campbell et al., 2004). M. Miroddi et al. / Journal of Ethnopharmacology 150 (2013) 791–804 795

6. Preclinical data supporting pharmacological effects extracts of passionflower with various flavonoid and GABA concentrations revealed different anticonvulsant properties against The potential therapeutic properties of Passiflora incarnata, PTZ-induced seizures in mice (Elsas et al., 2010). In another reported extensively in folk medicine, have been evaluated by experiment, a hydroethanolic extract significantly reduced PTZ- modern preclinical pharmacological studies with the aim of induced seizures and ameliorated associated post-ictal depression, characterising pharmacological activities (Table 2). Although its which diazepam usually worsens (Singh et al., 2012). Furthermore, extracts have been tested in numerous preclinical experiments, Passiflora incarnata was shown to possess analgesic action, increas- the mechanism of action of the extract is still under discussion. ing the nociceptive threshold in the tail-flick and hot-plate tests in The well-known sedative action has been demonstrated in various rats (Speroni and Minghetti, 2007). experiments conducted on mice and rats (Soulimani et al., 1997; Asignificant body of scientific literature highlighted the preclini- Speroni and Minghetti, 2007). Passionflower extracts were shown to calevidenceregardingthebeneficial properties of passionflower as a significantly prolong the sub-hypnotic pentobarbital-induced sleep treatment for addictive behaviours linked to substances such as (Soulimani et al., 1997). Other experiments demonstrated, in contrast amphetamine, nicotine, cannabis and ethanol, and benzodiazepines with previous evidence, that the flavonoids apigenin and chrysin (Capasso and Sorrentino, 2005; Dhawan et al., 2002a,b,c; Dhawan present in Passiflora incarnata did not significantly influence various and Sharma, 2003). In particular, BZF has been tested in various sleep parameters such as sleep duration (Zanoli et al., 2000), and sleep experiments for its ability to counter chronic drug use and substance onset latency, number of awakenings, duration of rapid eye movement dependence (Dhawan et al., 2003a). An aqueous passionflower (REM) and non-REM sleep were measured via electroencephalogra- extract was demonstrated to antagonise the locomotor sensitisation phy. This discrepancy might be related to the variability of extract in a group of rats with previously developed nicotine dependence constituents and to the small sample size of 8–12 rats, preventing the (Breivogel and Jamerson, 2012). The chronic co-administration of the observation of statistically significant differences between treatment BZF moiety along with morphine significantly attenuated the occur- conditions (Shinomiya, et al., 2005). rence of signs of morphine dependence and naloxone-precipitated Related to effects on sleep, anxiolytic activity is one of the most withdrawal jumps in mice. BZF-morphine co-treatment also reduced intensively investigated pharmacological roles of Passiflora incarnata the induction of tolerance measured using the tail-flick test (Dhawan (Dhawan et al., 2001c; Miyasaka et al., 2007). As some studies et al., 2002d). In another experiment, BZF exerted protective action showed that pre-administration of flumazenil, the antagonist of the against the development of Δ-9-tetrahydrocannabinol (THC) toler-

GABAA benzodiazepine binding site receptor, attenuates in vivo the ance, preventing the expression of the typical signs of withdrawal anxiolytic effect of Passiflora incarnata,passionflower and diazepam (Dhawan et al., 2002b). Administration of BZF together with nicotine were assumed to share the same mechanism of action (Medina et al., showed beneficial effects preventing the development of nicotine 1990; Grundmann et al., 2008). Dysfunction of the GABA system is tolerance and dependence. The severity and intensity of nicotine implicated in many neuropsychiatric conditions, including anxiety cessation withdrawal behaviours were significantly reduced in the and depressive disorders. Numerous pharmacological effects of group of mice treated with nicotine and BZF compared to the group Passiflora incarnata are mediated via the modulation of the GABA that received nicotine alone (Dhawan et al., 2002c). The passion- system, including affinity to the GABAA and GABAB receptors and flower BZF compound can decrease the levels of anxiety measured effects on GABA uptake. It appears to be unlikely that Passiflora using the EPM in ethanol-dependent mice. Additionally, mice treated incarnata extract acts by binding to the benzodiazepine site. How- with ethanol-BZF combinations exhibited less dependence and fewer ever, it is plausible that binding to the GABA-site of the GABAA withdrawal signs in comparison to the group of mice that only receptor is one mode of action of the plant extract (Appel et al., 2011). received ethanol, and these effects were dose-dependent. The signs Anxiolytic activity has been assessed in a series of in vivo experi- of diazepam dependence and cessation were less severe in mice ments based on various experimental animal models such as the treated with BZF (Dhawan, 2003b). Elevated Plus Maze (EPM) Grundmann et al. 2009 test, the staircase The administration of a passionflower extract can influence test and the light/dark box choice test (non-familiar environmental sexual behaviour in experimental animals, increasing the number tests). Soulimani et al. (1997) treated mice with a lyophilised of mounts, even though the sedative effect dominates over the hydroalcoholic extract or an aqueous extract of the aerial parts of “aphrodisiac effect” at high doses (Dhawan et al., 2003c). Studies this medicinal plant and subjected the mice to the staircase test of aging showed that the BZF moiety can counteract the detri- (non-familiar environmental test) and the light side of the light/dark mental effects on libido, fertility, and sperm count caused by box choice test (non-familiar environmental test). Both extracts chronic ethanol and nicotine consumption in 2 years old male rats exhibited anxiolytic properties, with decreases in rears and steps (Dhawan and Sharma, 2002a; Dhawan et al., 2003e). climbed in the staircase test and decreases in rears and locomotion in In experimental studies, a methanol extract demonstrated anti- the free exploratory test (Soulimani et al., 1997). The anxiolytic effect, tussive action in a murine model of sulphur dioxide-induced cough as assessed in mice by the EPM test, is lower for extracts obtained (Dhawan and Sharma, 2002b), and antiasthmatic dose-dependent from roots and flowers, which contain lower amounts of active action against acetylcholine-induced bronchospasms in guinea pigs compounds, making it desirable to separate the most active parts to (Dhawan et al., 2003d). Potential beneficial metabolic effects have maximise the anxiolytic action of extracts (Dhawan, 2010). been suggested by the demonstration of anti-hyperglycaemic and Among the chloroform, butanol, and petroleum ether fractions hypolipidemic actions on streptozotocin-induced diabetic mice (without BZF-like compounds) of a hydroethanol extract of Passiflora (Gupta et al., 2012). Two chemical compounds present in passion- incarnata, the chloroform fraction exerted the highest sedative effect flower extracts, chrysin and apigenin, have been found to exhibit in mice (Holbik, et al., 2010). Elsas et al. tested five different extracts antitumoural activity by inhibiting the growth of breast carcinoma of passionflower on rats and measured anxiety using EPM. Surpris- cells, human thyroid cancer cells and human prostate tumours ingly, the results showed anxiogenic activity for every extract. This (Ingale and Hivrale, 2010). unexpected anxiogenic action could be due to the lower baseline anxiety levels compared with the higher baseline levels of anxiety measured in other animal studies (Elsas et al., 2010). 7. Overview of clinical studies Speroni et al. observed the efficacy of Passiflora incarnata in the control of convulsions induced by pentylenetetrazole (PTZ) Passiflora incarnata has long been used in the folk medicine of (Speroni and Minghetti, 2007). More recently, five different West India, Mexico, the Netherlands, South America, Italy and 796 Table 2 Preclinical data about pharmacological activities of Passiflora incarnata L.

Pharmacological Tested extract or other derivative product In vitro/in vivo Model Administration Dose range Active concentration Reference activity (in vivo)

Anxyolitic activity Methanol extract of aerial parts In vivo Elevated Plus Maze test in Oral 10 mg/kg 10 mg/kg Dhawan et al., 2001a mice Methanol extract of aerial parts and In vivo Elevated Plus Maze test in Oral 100, 125, 200 and 300 mg/ 100, 125, 200 and 300 mg/ Dhawan et al., 2001b underground parts mice kg for both aerial and kg underground parts extract MeOH extract Water In vivo Elevated Plus Maze test in Oral 75, 100, 125, 200 and 75, 100, 125, 200 and Dhawan et al., 2001c Petrol extract CHCl 3 extract mice 300 mg/kg 300 mg/kg Mother tincture vs methanol extract of aerial In vivo Elevated Plus Maze test in Oral Mother tincture:100, 200, Mother tincture:100, 200, Dhawan et al., 2002c parts mice 300, and 400 mg/kg 300, and 400 mg/kg Methanol extract: Methanol extract: 125 mg/kg 125 mg/kg Fractions of hydroethanolic extract: In vivo Elevated Plus Maze test in Oral Fractions of total extract Fractions of total extract Sampath et al., 2011 791 (2013) 150 Ethnopharmacology of Journal / al. et Miroddi M. – Butanol fraction (BF) mice (rispectively150mg, (rispectively 150 mg/kg, – Petroleum ether fraction (PEF) 300 mg, 750 mg): 300 mg/kg, 750 mg/kg): – Chloroform fraction (CHCl3) – BF: 2.1 mg, – BF: 2.1 mg, 4.2 mg,10.5 mg 4.2 mg,10.5 mg – PEF: 0.17 mg 0.34 mg – PEF: 0.17 mg 0.34 mg 0.85 mg 0.85 mg – CHCl3: 0.15 mg 0.30 mg – CHCl3: 0.15 mg 0.75 mg 0.30 mg 0.75 mg

Sedative effect 0.5% carboxymethyl cellulose (CMC) In vivo Rat model of sleep Oral 300, 1000, 3000 mg/kg 300, 1000, 3000 mg/kg Shinomiya et al., disturbance 2005 Modulation GABA Dry extract (DER¼5-7:1, extraction solvent: 50% In vitro ex vivo Rat brain neurons N/A 0,1–1000 mcg/ml 0,1–1000 mcg/ml Appel et al., 2011 system ethanol (V/V)) (hippocampus and cerebellum) Anticonvulsivant/ Hydro-alcoholic extract In vivo Pentylentetrazole (PTZ) Intraperitoneal 0.4–0.05 mg/kg 0.4–0.05 mg/kg Nassiri-Asl et al., anti-epileptic induced seizures model in 2007 activity (and mice positive effect on Hydro-alcoholic extract In vivo Pentylentetrazole (PTZ) Intracerebroven- 0.125, 0.25, 0.55 and 0.125, 0.25, 0.55 and Nassiri-Asl et al., post-ictal induced seizures model in tricular 1.5 mcg 1.5 mcg 2007

depression) rats – Hydro- alcoholic extract Pentylentetrazole (PTZ) Intraperitoneal 150, 300 and 600 mg/kg 150, 300 and 600 mg/kg Singh et al., 2012 804 induced seizures model in In vivo Elevatedrats Plus Maze test in Oral – -10, 20 and 50 mg/kg of 10, 20 and 50 mg/kg Dhawan et al., 2002a Drug/substance extractBenzoflavone (BZF) moiety from methanol mice in which anxiety was twice daily for 7 days reversal effects on induced by withdrawn after – 10, 20 and 50 mg/kg on withdrawal an addictive dose 2 g/kg, bid 6th day of ethanol for 6 days of ethanol Benzoflavone (BZF) moiety from methanol In vivo Detrimental effects upon Oral 10 mg/kg for 7 days 10 mg/kg Dhawan et al., 2002d extract the libido, fertility, and sperm count in 3 groups of male rats treated with: – ethanol 3 g/kg, p.o. – nicotine 2 mg/kg, s.c. – ethanol 3 g/kg, p.o.þ nicotine 2 mg/kg, s.c. Benzoflavone (BZF) moiety from methanol In vivo Withdrawal in mice treated Oral 10, 50 and 100 mg/kg doses 10, 50 and 100 mg/kg Dhawan and Sharma, extract with 10 mg/kg dose of along with 10 mg/kg doses along with 10 mg/kg 2002b morphine for 9 days. Tail- flick and naloxone precipitated withdrawal jumps. Benzoflavone (BZF) moiety from methanol In vivo Withdrawal in mice treated Oral a 10- or 20-mg-kg -1 twice- 10- or 20-mg-kg -1 Dhawan et al., 2002b extract with addictive dose of daily for 6 days. delta9- tetrahydrocannabinol (delta9-THC) Benzoflavone (BZF) moiety from methanol In vivo Withdrawal in mice treated Oral 10, 50 or 100 mg/kg 10, 50 or 100 mg/kg Dhawan et al., 2003c extract with diazepam addictive dose Acqueous extract In vivo Locomotor activity in rats Oral 800 mg/kg of one dose 800 mg/kg Breivogel and treated with nicotine Jamerson, 2012

addictive dose 791 (2013) 150 Ethnopharmacology of Journal / al. et Miroddi M. Aphrodisiac activity Methanol extract In vivo Mounting behaviour with Oral 75, 100 and 150 mg/kg 75, 100 and 150 mg/kg Dhawan et al., 2003a non-oestrous female mice 1 10 and 20 mg/kg 1 Dhawan et al., 2003b Aphrodisiac activity Benzoﬂavone (NZF) moiety from methanol In vivo Mounting behaviour of rats Oral 10 and 20 mg/kg (restoration sexual extract treated with addictive doses decline after delta- of delta-9-THC with non- 9-THC) oestrous female rats – decrease in sperm count – number of impregnated pro-oestrous female rats

Anti-tussive effect Methanol extract of the leaves In vivo Sulphur dioxide-induced Oral 100 and 200 mg/kg 100 and 200 mg/kg Dhawan et al., 2003d cough in mice Anti-asthmatic effect Methanol extract of leaves In vivo Acetylcholine chloride Oral 50, 100 and 200 mg/kg 50, 100 and 200 mg/kg Dhawan et al., 2003d induced-bronchospasm in guinea-pigs Anti-diabetic activity Methanolic extract aerial parts petroleum ether In vivo Streptozotocine induced Oral 100 and 200 mg/kg for 15 100 and 200 mg/kg for 15 Gupta et al., 2012 (200 ml) and methanol (200 ml). diabetes in mice days days – 804 797 798 Table 3 Summary of clinical trials on Passiﬂora incarnata L.

Reference Study Condition Participants Age (treatment Treatment group Control group Treatment Outcomes measures Main results design and sample group/control duration size group) in years (treatment/ control)

Schulz et al., 1998 “The quantitative EEG as RCT; Healthy 12 53.775.6 Passiflora i. 1200 mg Placebo or active Single Qualitative EEG (qEEG) Changes in qEEG consistent with a screening instrument to identify DB; CR subjects extract (drug-extract control administration and self-rating of sedative effects sedative effects of single doses of plant ratio: 5.9:1) plus (Diazepam after 3 days of alertness with a Visual extracts in comparison with diazepam” caffeine 100 mg 10 mg) plus wash-out other Analogue Scale (VAS) caffeine 100 mg administration Akhondzadeh et al., 2001a “Passionflower RCT; Generalized 36 (18/18) Between 19 Passiflora i. extract 45 Oxazepam 4 weeks Hamilton Anxiety scale No significant difference between in the treatment of generalized anxiety: DB anxiety and 47 drops/day plus placebo 30 mg/day plus the two treatments

a pilot double-blind randomized disorders tablet 45 drops of 791 (2013) 150 Ethnopharmacology of Journal / al. et Miroddi M. controlled trial with oxazepam” (GAD) placebo “ fl 7 fl fi Akhondzadeh et al., 2001b Passion ower RCT; Opiates 65 (30/35), 34.8 7.678.1 Passi ora i. extract 60 Placebo 60 drops 2 weeks Short Opiate Same ef cacy on physical in the treatment of opiates withdrawal: DB addiction 30 pt. 35.9 drops plus clonidine plus clonidine Withdrawal Scale symptoms of withdrawal. a double-blind randomized controlled completed tablet 0.8 mg/daily tablet 0.8 mg/ (SOWS) Passiflora i. plus clonidine showed trial” the trial daily a more significant improvement (15/15) over clonidine on mental Akhondzadeh et al. 2005 “Passiflora RCT; Attention- 34 School-aged 0.04 mg/kg/day (twice Methylphenidate 8 weeks Parent and Teacher symptomsNo significant diffence between incarnata in the treatment of attention- DB deficit children (Age is daily) Passiflora i. 1 mg/kg/day ADHD Rating Scale the two treatment groups on deficit hyperactivity disorder in children hyperactivity not expressed extract (twice daily) Parent and Teacher Rating Scale and adolescents” disorder in years) scores (ADHD) Movafegh et al., 2008 “Preoperative oral RCT; Presurgery 60 (30/30) 32.074.6 Passiflora i. extract Placebo Single Psychomotor function Reduction of anxiety without Passiflora Incarnata reduces anxiety in DB anxiety 31.7 75.1 500 mg administration was assessed with the sedation ambulatory surgery patients: a double- Trieger Dot Test and the blind, placebo-controlled study” Digit-Symbol Substitution Test Fahami et al., 2010 “A comparative study RCT Menopausa 59 (29/30) 51.773.3 30 mg, 20% Pass P drop 160 mg 6 weeks Cooperman's index for Decrease of score of menopause on the effects of Hypericum Perforatum 51.8 72.6 (a Passiflora i. extract), effervescent menopausal symptoms symptoms in the two treatment and passion flower on the menopausal 10 drops, three times tablet of groups symptoms of women referring to Isfahan daily and 30 drops Hypericum p.

” – city health care centers before sleeping (three times 804 RCT; Sleep 41 22.7376.22 Passiflora i. teabags Petroselinumdaily) c. 1 week, after PSG recording (for Improvement of sleep quality. No Ngan and Conduit, 2011 “A Double-blind,DB disorders (containing 2 g of dried teabags 1 week of objective PSG sleep effects on STAI Placebo-controlled Investigation of the plant parts) (containing 2 g of wash-out measures) for 10 pt, Effectsower) of Passi Herbalflora incarnataTea on Subjective dried plant parts) another 1 week sleep diary, State Sleep(Passion Qualityfl ” Anxiety Inventory score (STAI) Aslanargun et al., 2012 “Passiflora RCT; Pre-spinale 60 (30/30) 50 (26–55) 44 Passiflora i. 700 mg/ Placebo Single State Anxiety Inventory Suppression of anxiety without incarnata Linneaus as an anxiolytic DB anaesthesia (25–55) 5 ml aqueous extract administration score changing psychomotor before spinal anaesthesia” anxiety (median, performance, sedation level, or minimum an hemodynamics maximum in brackets)

RCT¼randomized controlled trial; DB¼double blind; CR¼crossover. M. Miroddi et al. / Journal of Ethnopharmacology 150 (2013) 791–804 799

Argentina for the treatment of bronchitis, asthma, whooping 3 2 2 2 2 2 2

cough, pneumonia, nervousness and insomnia. Furthermore, this 1 ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ 0 0 0 0 0 0 plant is generally believed to possess sedative, antispasmodic and 0 þ þ þ þ þ þ þ 1 1 0 0 0 0 mild anti-microbial effects. 0-1 0 þ þ þ þ þ þ þ þ 0 0 0 0 0 0 Currently, products containing passionﬂower extracts are 0 0 þ þ þ þ þ þ þ þ 1 0 1 1 1 1 mainly utilised in modern phytotherapy as mild sedatives and 1 1 þ þ þ þ þ þ þ þ anxiolytic agents. The results from various clinical trials support Jadad score this use by demonstrating potential effects for the treatment of generalised anxiety disorder, pre-surgery anxiety, insomnia, attention-deﬁcit hyperactivity disorder, opiate withdrawal to-treat – symptoms and control of menopausal symptoms (Tables 3–5) (Nassiri-Asl et al., 2007). N/A 1 sample? Was an analysis conducted on the intention N/A 1

8. Anxiety (general anxiety disorder and pre-operative anxiety)

Anxiety disorders are the most prevalent psychiatric disorders (Kessler et al., 2010), and this spectrum of pathologies imposes high individual and societal burdens, sometimes becoming chronic the trial) Was the number of withdrawals/dropouts in each group mentioned? and disabling. These disorders impose further costs including the trial) hospitalisation, prescription medications, decreased productivity, absenteeism from work, and sometimes suicide (Movafegh et al., 2008). Different anxiety disorders have the following common features: excessive, irrational fear and avoidance of anxiety triggers (American PA, 2013 DSM-5 2013). Benzodiazepines (BZDs) are a common class of drugs used to cure anxiety disorders. Although Was the method of double blinding described and appropriate? these drugs are effective, BZD treatment suffers from several problems: a signiﬁcant percentage of patients are non-responders (approximately 25%), the development of tolerance and potential dependence; and sedation, resulting in cognitive and psychomotor

impairment. For this reason, safe alternative treatments are desired Was the trial described as double-blind? (Miyasaka et al., 2007; Movafegh et al., 2008; Koen and Stein, 2011). Some clinical trials have been performed to assess the putative anxiolytic effect of Passiflora incarnata already reported in folk medicine. One of these trials was designed to evaluate Passiflora incarnata treatment of Generalised Anxiety Disorder (GAD), and another two clinical trials were performed to assess its effective- Was the treatment allocation concealed? ness in treating pre-surgery anxiety. Akhondzadeh et al. (2001a,b) compared the supposed antianxiety effect of an extract of Passi- flora incarnata with the benzodiazepinic drug oxazepam in a double-blind randomised clinical trial carried out by recruiting 36 patients suffering from GAD. Patients were enroled if they matched the following inclusion Was the randomization procedure described and was appropriate? criteria: previous diagnosis of GAD according to DSM IV criteria (duration of illness at least 6 months) and a score of 14 or more measured by the Hamilton Anxiety Rating Scale. History of a serious suicide attempt or current acute suicidal ideation, psychosis, major Yes No Not reported Yes Not reported Not reported Not reported 1 Was the trial described as randomized? No N/A Not reported Yes Not reported Not reported Not reported 1 depression, substance abuse and dementia were considered as exclusion criteria. In a 4-week trial, a group of 18 volunteers was treated with a passionflower extract (commercialised in Iran as PassipayTM Iran Daroo) at a dose of 45 drops/day plus placebo tablet, and another 18 volunteers received 30 mg oxazepam per day plus placebo drops. The decrease in the HAM-A score from baseline was used as the main response measure. The patients were assessed Description not adequate Yes Yes Yes Not reported No N/A Yes Not reported 1 Yes Yes Yes Not reported Yes Not reported Yes (all pt completed Yes Yes No Not reported Yes Not reported Yes Yes 1 Yes Yes No Not reported Yes Not reported Yes Not reported 1 Description not adequate Yes Yes Yes Not reported Yes Not reported Yes (all pt completed at baseline and 4, 7, 14, 21 and 28 days after the beginning of the Was similarity between the two (or more) groups at baseline? treatment. Four subjects dropped out of the trial due to non- compliance (two from each group), for a total of 32 patients completing the trial. The results demonstrated that both herbal extract and oxazepam exerted positive effects, producing similar reductions in HAM-A scores with respect to baseline. In particular, oxazepam reduction was evident starting from day 4, leading to a more rapid onset of action. The results indicated that Passiflora incarnata is as effective as oxazepam for the treatment of GAD. Ngan and Conduit, 2011 Fahami et al., 2010 Movafegh et al., 2008 Akhondzadeh et al. 2005 Akhondzadeh et al., 2001b Akhondzadeh et al. 2001a Yes Yes No Not reported Yes Not reported Not reported Not reported 1 Schulz et al., 1998 Aslanargun et al., 2012 Reference

Patients treated with the extract experienced a small but Table 4 Quality assessment according to Jadad Scale. 800 M. Miroddi et al. / Journal of Ethnopharmacology 150 (2013) 791–804

Table 5 Section 4 of Elaboration of CONSORT Items for Randomized Controlled Trials of Herbal Medicine Interventions.

Reference Herbal medicinal Characteristics of the Dosage regimen and Qualitative Placebo/control Group Practitioner product name herbal product quantitative description testing (rationale for the type of control or placebo used)

Schulz et al., 1998 Yes (only name of Yes Yes No No No the manufacturer) Akhondzadeh et al. 2001a No No Yes No No No Akhondzadeh et al., 2001b No No Yes No No No Akhondzadeh et al. 2005 No No Yes No No No Movafegh et al., 2008 Yes No Yes No No No Fahami et al., 2010 Yes No Yes No No No Ngan and Conduit, 2011 Yes (only name of Yes Yes No No No the manufacturer) Aslanargun et al., 2012 YesNoNoNoNoNo statistically significant impairment of job performance compared tapping test (FTT) were evaluated. All tests (STAI-S2, STAI-T2, PAT2, with the oxazepam group. No other significant differences were and FTT2) were repeated for a second time, just before spinal observed between the two treatments in terms of side effects anaesthesia. The psychomotor function was again evaluated at the (Akhondzadeh et al., 2001b). end of the operation and 60 min after the operation. A statistically The anxiolytic activity of passionflower has been tested in two significant difference was observed between the two groups in the clinical studies conducted on patients undergoing surgery. One increase in the State Anxiety Inventory (STAI-S) score obtained just study was designed with the aim of comparing the effect of oral before spinal anaesthesia when compared to the baseline. No administration of a Passiflora incarnata extract with placebo as a statistically significant difference from baseline was observed in premedication before anaesthesia. The study enroled 60 patients psychomotor function for either group. Furthermore, no statisti- (aged between 25 and 45 years) with ASA (American Society of cally significant difference was observed between groups in terms Anaesthesiology patient classification status) physical status (Pt) I of the characteristics of the sensory and motor blocks, the time to and II (ASA I corresponds to normal healthy Pt; ASA II corresponds first analgesic requirement, the time to discharge, and side effects. to Pt with mild systemic disease but no functional limitation) Placebo and Passiflora. incanata extract resulted in comparable side undergoing inguinal herniorrhaphy. The subjects were randomly effects, with no observations of nausea, vomiting, respiratory depres- allocated in two groups of 30, one receiving Passiflora incarnata sion, shivering, or postoperative complications. The results suggested (500 mg, Passipay™) 90 min before the surgical operation, with that passionflower treatment reduces clinical symptoms anxiety each tablet containing 1.01 mg of benzoflavone (BZF). The other before spinal anaesthesia without affecting psychomotor function, group of 30 patients received a placebo. Anxiolytic and sedative sedation level, or hemodynamic parameters (Aslanargun et al., 2012). effects were assessed, in addition to psychomotor performance and While the clinical studies described above investigating the discharge time. A numerical rating scale (NRS) was used to assess effects of passionflower on anxiety are well designed, some weak each patient's anxiety and sedation before and 10, 30, 60, and 90 min points are evident. The sample of patients in the study of GAD is after premedication. Psychomotor function was assessed with the much too small, and none of these three studies describe rando- Trieger Dot Test (TDT) and the Digit-Symbol. The TDT deviation misation methods. A major limitation of these studies is that for represents the cumulative distance (in millimetres) between the the most part they do not contain any description of the type of drawn line and missed dots. The DSST is a subtest of the Wechsler herbal preparation used, giving health professionals incomplete Adult Intelligence Scale, a timed pen-and-paper test in which information on the potential therapeutic use of the Passiflora patients are required to appropriately match numbers and symbols. incarnata products investigated in these studies. The trade name Furthermore, the time interval between arrival in the posta- of the preparation is reported without providing any information naesthesia care unit and discharge to home (discharge time) was on the part of the plant, the type and percentage of extraction recorded. The NRS anxiety scores were significantly lower in the solvent (alcohol, water, chloroform, etc.) used, and the drug extract passionflower group compared with the control group (Po0.001). ratio (D.E.R.). This information is fundamental to link the results No significant differences were observed in psychological variables with a well-defined herbal preparation. Only in this way will in the postanaesthesia care unit, and the recovery of psychomotor clinicians be able to know and identify what preparations derived function was comparable in both groups. Patients did not report from Passiflora incarnata can be effective in curing a specific side effects, although the sample size was very small. In conclusion, condition, in this case GAD. While more data on the product used using Passiflora incarnata as a premedication reduced anxiety within these studies may be available on the website of the company out causing sedation (Movafegh et al., 2008). that produces it, a detailed description of the extract is needed to Aslanargun et al. (2012) conducted a prospective, randomised, enable a more complete evaluation of clinical efficacy. The more double-blind placebo-controlled study on 60 patients between 25 recent study by Aslanargun on preoperative anxiety is an exception, and 55 years of age who underwent regional anaesthesia with the as the ratio between the extract and water is reported and the aim of evaluating whether treatment with Passiflora incarnata randomisation method is adequately described. Neither of these extract before spinal anaesthesia could reduce anxiety. This study studies adequately describes how the sample size was determined. included ASA I–II patients. The participants, allocated in 2 groups In the Movafegh et al. trial, blinding is mentioned but the adopted using a random procedure, received the medication under inves- procedure is not sufficiently described. tigation (700 mg/5 ml of an aqueous extract of passionflower, produced by Sandoz, Kocaeli, Turkey) or a corresponding identical placebo, 30 min before the spinal anaesthesia baseline. Hemody- 9. Treatment of opiate withdrawal namic parameters, State-Trait Anxiety Inventory (STAI) score, alertness-sedation score (OAA/S), and psychomotor function mea- Opiate addicts and dependent subjects who attempt to quit sured using the perceptive accuracy test (PAT) and the finger opiate consumption commonly experience withdrawal syndrome. M. Miroddi et al. / Journal of Ethnopharmacology 150 (2013) 791–804 801

During the process of detoxification, these individuals can suffer Cooperman's Index for menopause symptoms at the three stages of from anxiety and sleep disorders, but the use of benzodiazepines pre-intervention, the third week of intervention, and the sixth week is not indicated because this class of drugs can induce dependence of intervention. The results showed that the average score for itself. Alternative non-opiate detoxification therapies have been menopause symptoms in the two treatment groups decreased tested to overcome some of the limitations of methadone-based significantly through the third and sixth weeks of the treatment detoxification regimens. Clonidine is an α2-adrenergic agonist that period (Po0.05), with no statistically significant differences observed attenuates symptoms caused by the disregulation of the noradre- between the two groups. The authors concluded that Hypericum nergic system. The main disadvantage of clonidine-based detoxi- perforatum and Passiflora incarnata can exert beneficial effects on fication, in addition to hypotensive side-effects, is the lack of precocious menopause symptoms (vasomotor signs, insomnia, effectiveness in addressing mental symptoms. depression, anger, headaches, etc.) and that health professionals can To verify the possible adjuvant activity of an extract of Passiflora use them as an alternative to hormone therapy (Fahami et al., 2010). incarnata on the treatment of opiate withdrawal based on cloni- The analysis of this study reveals several critical points. The dine, a clinical double-blind randomised trial vs. placebo has been randomisation procedure is not described, and no placebo treat- performed. A total of 65 participants with opiate addictions were ment is included. The authors correctly report this issue, but there randomly assigned to treatment with Passiflora incarnata extract is no ability to compare the results in this study with the normal plus clonidine tablet or clonidine tablet plus placebo. The patients evolution of menopausal symptoms. As we highlighted for other were considered eligible if they met the DSM IV criteria for opiate studies, the herbal preparation is not described, and only the dependence. The severity of the withdrawal syndrome was mea- product name is provided. sured using a revised version of the Short Opiate Withdrawal Scale (SOWS) at baseline (day 0) and days 1, 2, 3, 4, 7 and 14 after the start of the treatment. Fifteen subjects dropped out from the 11. Treatment of insomnia/sleep disorders passionflower group and 20 from the placebo group over the course of the trial, leaving 30 subjects (15 per group). The results Sleep disturbances contribute to increased healthcare utilisa- showed that the group of patients treated with clonidine plus tion and associated morbidity, and consequently have major Passiflora incarnata extract exhibited earlier symptom reductions societal and individual impact. Several studies have examined the than patients treated with placebo and clonidine. Statistical possible sedative effects of Passiflora incarnata on human sleep. As analysis of data regarding mental and physical symptoms showed anxiety has been shown to be positively correlated with sleep that treatment consisting of Passiflora incarnata plus clonidine disturbance (Spoormaker and van den Bout, 2005; Spira et al., reduced mental symptoms (e.g., insomnia/sleeping problems, 2008), Schulz et al. investigated the potential effects of passion- dysphoria, anxiety, agitation, irritability and craving for sub- flower in improving sleep quality in humans as a secondary stances) to a greater extent than physical symptoms of opiate consequence of its anxiolytic effects (Schulz et al., 1998). withdrawal (Akhondzadeh et al., 2001a). A randomised double-blind vs. placebo clinical trial of twelve This clinical trial does not describe the randomisation and healthy females (age: 53.775.6 years) was conducted to study the blinding methods. The trial is characterised by a high number of effects of different medicinal herbs (including Passiflora incarnata) drop-outs. Because of the small “intention to treat group”, a small on sleep quality. The experiment was designed as a randomised number of patients were finally treated. For this reason, adding an crossover study with six treatments: placebo, diazepam, valerian “intention to treat” analysis could be useful. Details about the extract, lavandula extract, passionflower and kava–kava extract. characteristics of passionflower extract are not reported, and even Passiflora incarnata extract (drug-extract ratio: 5.9:1) was admi- the trade name is not indicated. The absence of this information nistered in a single dose of 1200 mg, and the effects were prevents other researchers from reproducing the study or finding compared with placebo and diazepam (10 mg). Quantitative EEG further information on the product. and the level of alertness (rated by a visual analogue scale) were measured at 120 and 180 min after the co-administration of the medication with 100 mg of caffeine. Diazepam, placebo and 10. Treatment of menopausal symptoms passionflower extract all exerted effects, producing a similar decrease in mental alertness. EEG did not show any effect of The increase in women's lifespans implies a major quality of life passion flower extract in comparison with placebo (Schulz et al., impact of the physiological changes and disorders related to meno- 1998). pause. Vasomotor disorders, sleep disorders and psychological Another randomised double-blind placebo control clinical study changes are prevalent in this period of life for women. Hormone tested the potential efficacy of passionflower on 41 volunteers therapy is a common treatment, and results in some unwanted effects suffering from primary insomnia, 14 males and 27 females, aged for most individuals. Herbal medicines can act as additional ther- 18–35 years. The treatment was based on an infusion of dried apeutic tools with fewer side effects than hormone therapy (Vesco Passiflora incarnata partsinteabags(eachcontaining2gofdried et al., 2007; Freeman et al., 2011). A clinical study compared the leaves, stems, seeds and flowers), and the placebo was parsley effects of two extracts derived from the medicinal herbs Hypericum teabags (each containing 2 g of dried Petroselinum crispum L.); both perforatum L. and Passiflora incarnata on menopausal symptoms. The with dosages of 3 cups of tea per day. PolySomnoGraphy (PSG) and entrance conditions for this study were as follows: women who subjective sleep parameters were analysed, but only 10 subjects experienced menopause in the last year and women who were in the underwent PSG testing. The results revealed that in subjects receiv- first 5 years of menopause. The study recruited 59 menopausal ing passionflower, only subjective sleep quality was significantly women and randomly divided them into two groups, with improved compared with the placebo group. Passiflora incarnata did 30 patients undergoing Hypericum perforatum treatment and 29 not lead to any significant changes in the PSG parameters. patients treated with Passiflora incarnata. The following doses were As reported noted in the study, the small sample size limits the administered: Hypericum perforatum, 160 mg effervescent tablet power of the statistical analysis to detect significant differences. In made by Goldaroo Company, three times a day; Passiflora incarnata, addition to this limitation only a portion of the sample was 30 mg, 20% Pass P dropTM, made by Iran Daroo Company, 10 drops, assessed by PSG. Furthermore, the fact that the patients were three times a day and 30 drops before sleeping. The women filled not adapted to sleeping in uncomfortable environments such as out an interview, Personal Characteristics Questionnaire, and the laboratory may have limited the treatment effectiveness. 802 M. Miroddi et al. / Journal of Ethnopharmacology 150 (2013) 791–804

The authors suggested that the administered dose may not have As we found in other studies, details about the characteristics of been sufficient because it was only administered in the night time the Passiflora incarnata extract are not reported, and even the to avoid daytime sedation (Ngan and Conduit, 2011). trade name is not indicated. Thus, it is difficult for other research- The article by Ngan et al. does not provide sufficient details ers to reproduce the results of this study. about the features of the herbal preparation, instead only indicat- ing the name of the manufacturer. Randomisation and blinding procedures were also not explained. According to several articles, a 13. Safety profile and pharmacovigilance data placebo should be an inert substance or procedure, and the placebo effect (or response) is the response following placebo No acute toxicity was observed after intraperitoneal injection of administration (Finiss et al., 2010). In the present clinical trial, the doses larger than 900 mg/kg in mice (Fisher et al., 2000). The acute placebo is an herbal preparation containing Petroliseum crispum, oral administration of the methanolic extract of Passiflora incarnata which does not fit the definition of placebo widely accepted by the in various doses of 50, 100, 200, 400, 800 and 1600 mg/kg did not scientific community, consequently revealing a substantive meth- lead to any mortality up to 7 days after treatment (Gupta et al., odological weakness. The article published by Schulz et al. pro- 2012). No case of overdose has been reported in humans, and the US vides little information regarding the extract used, and the patient Food and Drug Administration classified passionflower extracts as sample is highly limited, with only 12 subjects. On the other hand, “generally regarded as safe” (GRAS) (Burdock and Carabin, 2004). this study provides useful information because it compares the One case of toxicity has been published for a woman consuming effects of extracts obtained from different herbal medicines Passiflora incarnata at therapeutic doses of 500–1000 mg 3 times on sleep. daily. The authors did not provide details about the type of extract used to produce the tablets, but only reported that one tablet contained the “equivalent [of] 500 mg of the active ingredients” of 12. Treatment of ADHD the plant. A 34-year-old woman developed severe nausea, vomiting, drowsiness, prolonged QT and episodes of non-sustained ventricular Attention Deficit Hyperactivity Disorder (ADHD) is a psychiatric tachycardia. The possible association of symptoms with Passiflora condition characterised by age-inappropriate levels of inattention, incarnata was not recognised for several days, at which point she hyperactivity-impulsiveness or a combination of these problems required hospitalisation for cardiac monitoring and received intra- (Shaw et al., 2012). The symptoms of ADHD often lead to venous fluid therapy (Fisher et al., 2000). functional impairment in multiple domains and lower quality of In another case, a patient self-medicated with Valeriana officinalis L. life. Stimulants are currently the first-line treatment for ADHD. and Passiflora incarnata while on lorazepam treatment developed Nevertheless roughly 30% of children and adolescents are either handshaking, dizziness, throbbing and muscular fatigue within the non-responders or experience severe side effects, so the use of 32 h before clinical diagnosis. The patient's medical history revealed herbal medicine could provide therapeutic benefit. As Passiflora GAD but no neurological disorder. An additive or synergistic effect was incarnata is a folk remedy for anxiety and ADHD, its potential hypothesisedasthecauseofthesesymptoms.Theactivechemical beneficial activity against ADHD has been evaluated in a double- constituents of Valeriana officinalis and Passiflora incarnata might blind, randomised clinical trial on a sample of 34 children with enhance the action of benzodiazepine binding to the GABA receptors ADHD. This disorder was diagnosed according the Diagnostic and (Carrasco et al., 2008). Furthermore Passiflora incarnata is associated Statistical Manual of Mental Disorders (DSM IV). The authors with IgE-mediated occupational asthma and rhinitis (Giavina-Bianchi hypothesised that a therapy based on Passiflora incarnata tablets et al., 1997). A case of hypersensitivity with cutaneous vasculitis and could lead to clinical improvements in ADHD patients. The urticara has been reported, with lesions appearing over the shins and children were divided among two groups: group 1 received the ankles, and also over the shoulder and one thumb after the passionflower tablets 0.04 mg/kg/day (twice daily) and group ingestion of tablets containing Passiflora incarnata extract (Smith et al., 2 received methylphenidate tablets 1 mg/kg/day (twice daily), 1993). As passionflower may induce uterine contractions, the con- both for a duration of 8 weeks. The authors defined as outcome sumption of this herbal medicine is contraindicated during pregnancy measures the Parent and Teacher ADHD Rating Scale. A child (Fisher et al., 2000). psychiatrist assessed the children at baseline, 14, 28, 42 and 56 days after the treatment began. No significant differences were observed between the two medications in the Parent and Teacher 14. Conclusion Rating Scale scores over the course of the trial (F¼0.007, df¼1, p¼0.93; and F¼0.006, df¼1, p¼0.94, respectively), although Interest in the clinical use of medicinal plants has increased patients who received methylphenidate experienced decreased dramatically over the past decade throughout the world (Frass appetite and anxiety/nervousness more often than those in the et al., 2012), and the benefits of these products are increasingly Passiflora incarnata group. An intention to treat (ITT) analysis was cited in the media (Kelly et al., 2005). The high consumption of performed. Two patients dropped out from the methylphenidate these types of products by an extensive number of patients has led group and one from the passionflower group due to failure to to growing concerns about their efficacy and safety (Bishop and follow up, resulting in 31 patients completing the protocol. Lewith, 2010). In many countries, these products are regulated Although the number of dropouts in the methylphenidate group both as medicinal products and as food supplements, and they are was higher than that in the Passiflora incarnata group, no statis- often labelled as natural food supplements (Miroddi et al., 2013). tically significant differences have been reported between the two In light of its long tradition of use and the growing demand for branches of the study. In addition, decreased appetite and anxiety/ Passiflora incarnata derivative preparations, this study reviewed nervousness occurred more often in the methylphenidate group. and commented on the current knowledge provided by preclinical These results suggest that the main advantage of the Passiflora and clinical research on the effects of this plant. incarnata treatment is a more tolerable side-effect profile Although the data provided here show that this medicinal plant (Akhondzadeh et al., 2005). may exert beneficial effects in the treatment of several pathologi- The analysis of this study reveals critical issues including a lack cal conditions, further studies are needed to clarify issues regard- of description of randomisation and blinding procedures. The ing the composition of the phytocomplex, the replicability of authors correctly report the small patient sample as a limitation. preclinical experiments, the lack of translation of the preclinical M. Miroddi et al. / Journal of Ethnopharmacology 150 (2013) 791–804 803 results to humans, the lack of methodological accuracy in clinical Carratù, B., Boniglia, C., Giammarioli, S., Mosca, M., Sanzini, E., 2008. Free amino trials, and the types of extracts causing adverse effects. To date, no acids in botanicals and botanical preparations. J. Food Sci. 73, C323–C328. Clark, H.D., Wells, G.A., Huët, C., McAlister, F.A., Salmi, L.R., Fergusson, D., Laupacis, A., standardised composition has been defined for this plant, and the 1999. Assessing the quality of randomized trials: reliability of the Jadad scale. concentrations of the various chemical constituents in its prepara- Controlled Clin. Trials 20, 448–452. tions that are necessary to achieve specific pharmacological effects Dhawan, K., Kumar, S., Sharma, A., 2001a. Anti-anxiety studies on extracts of remain unknown. Furthermore, because the mechanisms of action Passiflora incarnata Linneaus. J. Ethnopharmacol. 78, 165–170. fl Dhawan, K., Kumar, S., Sharma, A., 2001b. Anxiolytic activity of aerial and under- of the different compounds present in Passi ora incarnata remain ground parts of Passiflora incarnata. Fitoterapia 72, 922–926. unclear, studies should be carried out to explore the structure– Dhawan, K., Kumar, S., Sharma, A., 2001c. Comparative biological activity study on activity relationships among the constituents. Passiflora incarnata and Passiflora edulis. Fitoterapia 72, 698–702. We evaluated the methodological accuracy of published clinical Dhawan, K., Kumar, S., Sharma, A., 2002a. Suppression of alcohol-cessation- oriented hyper-anxiety by the benzoflavone moiety of Passiflora incarnata trials on this plant according to current and consolidated guide- Linneaus in mice. J. Ethnopharmacol. 81, 239–244. lines for the reporting of the clinical efficacy of herbal medicine Dhawan, K., Kumar, S., Sharma, A., 2002b. Reversal of cannabinoids (delta9THC) by provided by the Consort Statement (Table 5)(Gagnier et al., 2006). the benzoflavone moiety from methanol extract of Passiflora incarnata Linneaus in mice: a possible therapy for cannabinoid addiction. J. Pharm. Pharmacol. 54, Furthermore, we assessed the methodological quality of clinical 875–881. studies using the Jadad Scale (Table 4)(Clark et al., 1999), finding Dhawan, K., Kumar, S., Sharma, A., 2002c. Comparative anxiolytic activity profile of that only one of the eight trials considered here had a score of 3 (a various preparations of Passiflora incarnata linneaus: a comment on medicinal – scoreZ3 means “good quality”), while the other studies had plants' standardization. J. Alternative Complementary Med. 8, 283 291. Dhawan, K., Sharma, A., 2002a. Prevention of chronic alcohol and nicotine-induced scores of 1 or 2. The clinical trials included in this review exhibit azospermia, sterility and decreased libido, by a novel tri-substituted benzo- crucial weaknesses such as insufficient details regarding the drug flavone moiety from Passiflora incarnata Linneaus in healthy male rats. Life sci. extract ratio, limited patient samples, no description of blinding 71, 3059–3069. and randomisation procedures, unclear placebo definition, and a Dhawan, K., Kumar, S., Sharma, A., 2002d. Reversal of morphine tolerance and dependence by Passiflora incarnata. A traditional medicine to combat morphine lack of intention to treat analysis. Thus, some of the potential addiction. Pharm. Biol. 40, 576–580. therapeutic effects of Passiflora incarnata need to be evaluated in Dhawan, K., Sharma, A., 2002b. Antitussive activity of the methanol extract of new studies. Passiflora incarnata leaves. Fitoterapia 73, 397–399. Dhawan, K., Kumar, S., Sharma, A., 2003a. Aphrodisiac activity of methanol extract In conclusion, this review highlights the fact that the common of leaves of Passiflora incarnata Linn. in mice. Phytother. Res. 17, 401–403. therapeutic uses of Passiflora incarnata are not sufficiently sup- Dhawan, K., 2003b. Drug/substance reversal effects of a novel tri-substituted ported by clinical evidence. Future research should be conducted benzoflavone moiety (BZF) isolated from Passiflora incarnata Linn.‚ a brief – using a more rigorous methodology with the ability to corroborate perspective. Addict. Biol. 8, 379 386. Dhawan, K., Dhawan, S., Chhabra, S., 2003c. Attenuation of benzodiazepine fl and ascertain the therapeutic potential of Passi ora incarnata. dependence in mice by a tri-substituted benzoflavone moiety of Passiflora incarnata Linneaus: a non-habit forming anxiolytic. J. Pharmacy Pharm. Sci. 6, 215–222. References Dhawan, K., Kumar, S., Sharma, A., 2003d. 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